Method for the preparation of esters of anhydroecgonine

ABSTRACT

The present invention discloses compounds of the formula any mixture thereof, or a pharmaceutically acceptable salt thereof; 
     wherein R, R 3 , and R 4  each have the meanings set forth in the specification. 
     The compounds possess valuable pharmaceutical properties as dopamine reuptake inhibitors.

CROSS-REFERENCE

This application is a 371 of PCT/U.S. 96/01277 filed Mar. 22, 1996.

The present invention relates to a novel process for the preparation ofesters of anhydroecgonine from cocaine and derivatives thereof. Estersof anhydroecgonine are useful intermediates in the preparation ofpharmaceutically active tropane derivatives.

BACKGROUND OF THE INVENTION AND PRIOR ART

Several publications describe conversions of cocaine to anhydroecgoninewhere the conversion is effected by heating cocaine in aqueous acid(hydrochloric or sulphuric acid) or with benzoic acid for several hours(de Jong, Recl. Trav. Chim. Pays-Bas, 56 (1937), pages 187-201 and Chem.Ber., 21 (1888), pages 3029-3045). At the time of the references citedabove, the analytical methods available for the qualitative andquantitative determination of chemical compounds were limited, whichmakes the results obtained highly uncertain. Furthermore there is a lackof precise descriptions of how the reactions were carried out.

Several attempts to convert ecgonine or cocaine to anhydroecgonine inalkaline solutions or by heating in water, giving poor results, havealso been described. In fact it seems that alkaline solutions favourisomerisation (de Jong, Recl. Trav. Chim. Pays-Bas, 56 (1937), pages192-194.

In later references Anhydroecgonine and esters thereof have beenprepared by hydrolysis of cocaine in aqueous hydrochloric acid followedby dehydration with phosphorus oxychloride (J. Amer. Chem. Soc., 82(1960), page 4643 and EP-A1-604 355 ). Although both the hydrolysis ofcocaine and the dehydration of ecgonine produces high yields, it is aserious drawback to this method that the reaction mixture becomes syrupyduring the dehydration step which makes stirring almost impossible.Using SOCl₂ as dehydrating agent causes similar problems.

Neither of these methods are thus suitable for large-scale production.

It has now surprisingly been found that esters of anhydroecgonine can beprepared in large-scale from cocaine or derivatives thereof using aconvenient, high-yielding, one-pot synthesis.

The esters prepared according to the invention are useful intermediatesin the preparation of pharmaceutically active tropane derivatives, seeEP-A1-604 355).

OBJECTS OF THE INVENTION

It is an object of the invention to provide a novel method for preparingcarboesters of anhydroecgonine, which is convenient, high-yielding andsuitable for large-scale productions. Additional objects will be obviousto a person skilled in the art.

SUMMARY OF THE INVENTION

The invention then, inter alia comprises the following:

A process for the preparation of esters of anhydroecgonine having theformula ##STR1## any of its enantiomers or any mixture thereof, or asalt thereof, wherein R is alkyl, or optionally substituted aryl, orarylalkyl; comprising the step of reacting a compound of formula##STR2## any of its enantiomers or any mixture thereof, or a saltthereof, wherein R¹ is hydrogen, alkyl-CO--, or optionally substitutedaryl-CO--, or arylalkyl-CO--; with an alcoholate RO⁻, M⁺ wherein R is asdefined above and M⁺ is a counter ion, followed by isolation of theresulting compound either as the base or, if desired, in the form of asalt thereof;

such a process wherein the alcoholate is an alkalimetal alcoholate;

and such a process wherein the alkalimetal alcoholate is sodiumethanolate, potassium ethanolate, lithium ethanolate, sodiummethanolate, potassium methanolate, or lithium methanolate.

In the above definition of R and R¹, alkyl means a straight-chained orbranched chain of from one to six carbon atoms or cyclic alkyl of fromthree to seven carbon atoms, including but not limited to, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; methyl, ethyl, propyland isopropyl are preferred groups.

Aryl means an aromatic group, such as for example phenyl or napthylwhich may substituted one or more times with alkyl, alkoxy, halogen,amino, nitro, cyano and trifluoromethyl for example.

Examples of salts of the compounds of formula (I) and (II) are acidaddition salts including inorganic and organic acid addition salts suchas the hydrochloride, hydrobromide, phosphate, nitrate, perchlorate,sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate,benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate,stearate, succinate, glutamate, glycollate, toluene-p-sulphonate,formate, malonate, naphthalene-2-sulphonate, salicylate and the acetate.Such salts are formed by procedures well known in the art.

Other acids such as oxalic acid, may be useful in the preparation ofsalts useful as intermediates in obtaining compounds of the inventionand their pharmaceutically acceptable acid addition salts.

It will be appreciated by those skilled in the art that the compoundshaving the formula (I) and (II) contain several chiral centres and thatsuch compounds exist in the form of isomers (i.e. enantiomers). Theinvention includes all such enantiomers and any mixtures thereofincluding racemic mixtures.

Racemic mixtures can be resolved into the optical antipodes by knownmethods, for example by separation of diastereomeric salts thereof withan optically active acid, and liberating the optically active aminecompound by treatment with a base. Another method for resolvingracemates into the optical antipodes is based upon chromatography on anoptically active matrix. Racemic mixtures can thus be resolved intotheir optical antipodes, e.g. by fractional crystallization of d- orl-(tartrates, mandelates, or camphorsulphonate) salts for example.Racemic mixtures may also be resolved by the formation of diastereomericamides by reaction of the compounds with an optically active activatedcarboxylic acid, such as that derived from (+) or (-) phenylalanine, (+)or (-) phenylglycine, (+) or (-) camphanic acid, or by the formation ofdiastereomeric carbamates by reaction with an optically activechloroformate or the like.

Additional methods for the resolvation of optical isomers, known tothose skilled in the art may be used, and will be apparent to theaverage worker skilled in the art. Such methods include those discussedby J. Jaques, A. Collet, and S. Wilen in "Enantiomers, Racemates, andResolutions", John Wiley and Sons, New York (1981).

DETAILED DESCRIPTION OF THE INVENTION

The following scheme illustrates the process of the invention ##STR3##

The process of the invention is suitably effected by heating thereaction components in an anhydrous organic solvent. Suitable organicsolvents are for example an alcohol, such as methanol, ethanol,isopropanol or phenol, ethers such as diisopropylether, tetrahydrofuranor dioxan, amides such as dimethylformamide, esters such as ethylacetator halogenated-, aromatic- or aliphatic hydrocarbons such as chloroform,dichlormethan, benzene, toluene, xylene and hexane.

The reaction temperature depends on the solvent used.

The obtained anhydroecgonine ester can be isolated using conventionalmethods, such as extraction, distillation, crystallisation,chromatography etc.

Starting materials are commercially available or can be prepared fromcommercially available materials using conventional methods.

EXAMPLES

The invention will now be described in greater detail with reference tothe following example, which is given by way of illustration only andare not to be construed as limiting.

Anhydroecgonine Ethyl Ester ##STR4##

A solution of sodium ethanolate in ethanol was made by addition ofsodium (103 g, 4.5 mol) to absolute ethanol (3.25 l) stirred at refluxtemperature. When all sodium was reacted, the mixture was cooled to 70°C. and ethyl acetate (3 l) was added followed by cocaine hydrochloride(500 g, 1.47 mol)(optical active from natural sources, available fromBelgopia). This mixture was stirred at reflux temperature under anitrogen atmosphere for 2.5 hour, followed by slow addition of glacialacetic acid (150 ml, pH=7-8) to the warm mixture. Dry toluene (1.5 l)was added and an azeotrope of ethanol, ethyl acetate and toluene(temperature 30° C.) was distilled in vacuo (approximately 20 mbar).When approximately 2 l azeotrope has been collected, more toluene (2 l)was added and another portion (2 l) of azeotrope was distilled. This wasrepeated once more resulting in a total addition of 5.5 l toluene anddistillation of approximately 6 l azeotrope. The resulting suspension ofsodium chloride and sodium acetate in organic solvent was filtered andthe filtrate was washed twice with toluene. The combined organic phaseswere concentrated in vacuo resulting in a yellow to brown oil. This oilwas distilled at 15 mbar using a short vigreaux column, and ethylbenzoate was collected at 72-115° C., the vigreaux column was removedand the remanence was distilled at 0.2-0.5 mbar, and the title compoundwas collected at 67-78° C. as a clear slightly yellow oil. Yield 219.5g=77%.

I claim:
 1. A process for the preparation of esters of anhydroecgoninehaving the formula ##STR5## or a pharmaceutically acceptable acidaddition salt thereof, wherein R is alkyl, or optionally substitutedaryl, or arylalkyl; comprising the step of reacting a compound offormula ##STR6## or a pharmaceutically acceptable acid addition saltthereof, wherein R¹ is hydrogen, alkyl-CO--, or optionally substitutedaryl-CO--, or arylalkyl-CO--;with an alcoholate RO⁻, M⁺ wherein R is asdefined above and M⁺ is a counter ion, followed by isolation of theresulting compound either as the base or, if desired, in the form of apharmaceutically acceptable acid addition salt thereof.
 2. A process asin claim 1 wherein the alcoholate is an alkalimetal alcoholate.
 3. Aprocess as in claim 2 wherein the alkalimetal alcoholate is sodiumethanolate, potassium ethanolate, lithium ethanolate, sodiummethanolate, potassium methanolate, or lithium methanolate.
 4. A processfor the preparation of enantiomers of esters anhydroecgonine having thefollowing formula ##STR7## wherein R is alkyl, or optionally substitutedaryl, or arylalkyl comprising the step of reacting an enantiomer of acompound of formula ##STR8## wherein R¹ is hydrogen, alkyl-CO--, oroptionally substituted aryl-CO--, or arylalkyl-CO--;with an alcoholateRO⁻, M⁺ wherein R is a s defined above and M⁺ is a counter ion, followedby isolation of the resulting enantiomer.
 5. The process of claim 1,wherein the anhydroecgonine of formula (I) is ##STR9## and the compoundof formula (II) is ##STR10##